Mevalonate-independent methylerythritol phosphate pathway for isoprenoid biosynthesis. Elucidation and distribution

A long-overlooked metabolic pathway for isoprenoid biosynthesis, the mevalonate-independent methylerythritol phosphate (MEP) pathway, is present in many bacteria and in the chloroplasts of all phototrophic organisms. It represents an alternative to the well known mevalonate pathway, which is present in animals, fungi, plant cytoplasm, archaebacteria, and some eubacteria. This contribution summarizes key steps of its elucidation and the state-of-the-art knowledge of this biosynthetic pathway, which represents a novel target for antibacterial and antiparasitic drugs.

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Isoprenoid biosynthesis as a target for antibacterial and antiparasitic drugs: phosphonohydroxamic acids as inhibitors of deoxyxylulose phosphate reducto-isomerase

Biochemical Journal ◽

10.1042/bj20041378 ◽

2005 ◽

Vol 386 (1) ◽

pp. 127-135 ◽

Cited By ~ 73

Author(s):

Lionel KUNTZ ◽

Denis TRITSCH ◽

Catherine GROSDEMANGE-BILLIARD ◽

Andréa HEMMERLIN ◽

Audrey WILLEM ◽

...

Keyword(s):

Escherichia Coli ◽

Malaria Parasite ◽

Pathogenic Bacteria ◽

Isoprenoid Biosynthesis ◽

Methylerythritol Phosphate Pathway ◽

Methylerythritol Phosphate ◽

Parasite Plasmodium ◽

Parasite Plasmodium Falciparum ◽

Petri Dishes ◽

Antiparasitic Drugs

Isoprenoid biosynthesis via the methylerythritol phosphate pathway is a target against pathogenic bacteria and the malaria parasite Plasmodium falciparum. 4-(Hydroxyamino)-4-oxobutylphosphonic acid and 4-[hydroxy(methyl)amino]-4-oxobutyl phosphonic acid, two novel inhibitors of DXR (1-deoxy-D-xylulose 5-phosphate reducto-isomerase), the second enzyme of the pathway, have been synthesized and compared with fosmidomycin, the best known inhibitor of this enzyme. The latter phosphonohydroxamic acid showed a high inhibitory activity towards DXR, much like fosmidomycin, as well as significant antibacterial activity against Escherichia coli in tests on Petri dishes.

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Faculty Opinions recommendation of Isoprenoid biosynthesis via the methylerythritol phosphate pathway: the (E)-4-hydroxy-3-methylbut-2-enyl diphosphate reductase (LytB/IspH) from Escherichia coli is a [4Fe-4S] protein.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1013324.190005 ◽

2003 ◽

Author(s):

Haruo Seto

Keyword(s):

Escherichia Coli ◽

Isoprenoid Biosynthesis ◽

Methylerythritol Phosphate Pathway ◽

Methylerythritol Phosphate

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The mevalonate pathway but not the methylerythritol phosphate pathway is critical for elaioplast and pollen coat development in Arabidopsis

Plant Biotechnology ◽

10.5511/plantbiotechnology.18.0702a ◽

2018 ◽

Vol 35 (4) ◽

pp. 381-385 ◽

Cited By ~ 1

Author(s):

Keiko Kobayashi ◽

Masashi Suzuki ◽

Toshiya Muranaka ◽

Noriko Nagata

Keyword(s):

Mevalonate Pathway ◽

Methylerythritol Phosphate Pathway ◽

Methylerythritol Phosphate ◽

Pollen Coat

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Modulating the Precursor and Terpene Synthase Supply for the Whole-Cell Biocatalytic Production of the Sesquiterpene (+)-Zizaene in a Pathway Engineered E. coli

Genes ◽

10.3390/genes10060478 ◽

2019 ◽

Vol 10 (6) ◽

pp. 478 ◽

Cited By ~ 5

Author(s):

Francisco Aguilar ◽

Thomas Scheper ◽

Sascha Beutel

Keyword(s):

Essential Oil ◽

Metabolic Flux ◽

Mevalonate Pathway ◽

Terpene Synthase ◽

Methylerythritol Phosphate Pathway ◽

Main Compound ◽

E Coli ◽

Methylerythritol Phosphate ◽

Cosmetic Industry ◽

Multiple Copies

The vetiver essential oil from Chrysopogon zizanioides contains fragrant sesquiterpenes used widely in the formulation of nearly 20% of men’s cosmetics. The growing demand and issues in the supply have raised interest in the microbial production of the sesquiterpene khusimol, the main compound of the vetiver essential oil due to its woody smell. In this study, we engineered the biosynthetic pathway for the production of (+)-zizaene, the immediate precursor of khusimol. A systematic approach of metabolic engineering in Escherichia coli was applied to modulate the critical bottlenecks of the metabolic flux towards (+)-zizaene. Initially, production of (+)-zizaene was possible with the endogenous methylerythritol phosphate pathway and the codon-optimized zizaene synthase (ZS). Raising the precursor E,E-farnesyl diphosphate supply through the mevalonate pathway improved the (+)-zizaene titers 2.7-fold, although a limitation of the ZS supply was observed. To increase the ZS supply, distinct promoters were tested for the expression of the ZS gene, which augmented 7.2-fold in the (+)-zizaene titers. Final metabolic enhancement for the ZS supply by using a multi-plasmid strain harboring multiple copies of the ZS gene improved the (+)-zizaene titers 1.3-fold. The optimization of the fermentation conditions increased the (+)-zizaene titers 2.2-fold, achieving the highest (+)-zizaene titer of 25.09 mg L−1. This study provides an alternative strategy to enhance the terpene synthase supply for the engineering of isoprenoids. Moreover, it demonstrates the development of a novel microbial platform for the sustainable production of fragrant molecules for the cosmetic industry.

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From The Cover: Chlamydial histone-DNA interactions are disrupted by a metabolite in the methylerythritol phosphate pathway of isoprenoid biosynthesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0400754101 ◽

2004 ◽

Vol 101 (19) ◽

pp. 7451-7456 ◽

Cited By ~ 48

Author(s):

N. A. Grieshaber ◽

E. R. Fischer ◽

D. J. Mead ◽

C. A. Dooley ◽

T. Hackstadt

Keyword(s):

Isoprenoid Biosynthesis ◽

Dna Interactions ◽

Methylerythritol Phosphate Pathway ◽

Methylerythritol Phosphate

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The deoxyxylulose phosphate pathway of isoprenoid biosynthesis. Discovery and function of the ispDEFGH genes and their cognate enzymes

Pure and Applied Chemistry ◽

10.1351/pac200375020393 ◽

2003 ◽

Vol 75 (2-3) ◽

pp. 393-405 ◽

Cited By ~ 39

Author(s):

F. Rohdich ◽

Stefan Hecht ◽

Adelbert Bacher ◽

Wolfgang Eisenreich

Keyword(s):

Biosynthetic Pathway ◽

Mevalonate Pathway ◽

Isoprenoid Biosynthesis ◽

Catalytic Action ◽

Isopentenyl Diphosphate ◽

Dimethylallyl Diphosphate ◽

And Function

Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) serve as the universal precursors for the biosynthesis of terpenes. Besides the well-known mevalonate pathway, a second biosynthetic pathway conducive to IPP and DMAPP via 1-deoxy-d-xylulose-5-phosphate and 2C-methyl-d-erythritol-4-phosphate has been discovered recently in plants and certain eubacteria. 2C-Methyl-d-erythritol-4-phosphate, the first committed intermediate of the deoxyxylulose phosphate pathway, is converted into 2C-methyl-d-erythritol 2,4-cyclodiphosphate by the catalytic action of three enzymes specified by the ispDEF genes. The cyclic diphosphate is reductively opened by the IspG protein affording 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate. This compound can be converted into IPP as well as DMAPP by the catalytic action of IspH protein. The enzymes of this pathway are potential targets for novel antibacterial, antimalarial, and herbicide agents.

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